Correlational evidence of structural and functional changes in both the OFC and striatum in OCD has accumulated over the past 30 years4. More recent rodent studies have functionally linked these regions to OCD-relevant behavior51 and highlighted a critical role for excitatory synaptic signaling through the use of transgenic knockout mice lacking proteins involved in normal excitatory synaptic neurotransmission33–35,52,53. Furthermore, genetic studies of OCD subjects frequently identify associations with genes involved in excitatory synaptic signaling11,12,16,17,19–22,54. Consistent with these findings, we observed alterations of transcripts involved in synaptic signaling in OCD subjects via gene-set analysis. Of the 32 significant gene-sets we identified, 16 were classified as involved in synaptic neurotransmission (Fig. 2). Genes in these sets were disproportionately downregulated (Table S3b), consistent with our previous qPCR findings in the tissue from these same subjects36 and with genetic knockout mice that display compulsive behavior33,35. Future molecular studies must investigate how downregulation of synaptic gene expression could lead to observed hyperactivity in the OFC and striatum of OCD patients. In the OFC, hyperactivity may be driven through a decrease in expression patterns representative of
